Authors: Sara C. LaHue
Categories: Article
Source: Continuum (Minneapolis, Minn.)
Authors: Sara C. LaHue
This article reviews neurologic complications associated with pregnancy and menopause, the influence of pregnancy and menopause on preexisting neurologic disorders, and the management of neurologic disorders during pregnancy and menopause.
Pregnancy and menopause can significantly impact neurologic health. Neurologic consultation regarding mode of delivery and anesthesia in patients with neurologic conditions is common, and very few neurologic conditions warrant cesarean delivery. Pregnancy is not a contraindication to acute ischemic stroke therapies or targeted temperature management after cardiac arrest. Both pregnancy complications and earlier age at menopause are associated with worse cognitive and cerebrovascular outcomes later in life. Hormone therapy is approved by the US Food and Drug Administration (FDA) for the treatment of vasomotor symptoms, osteoporosis prevention, and genitourinary syndrome of menopause, all of which are conditions that may be exacerbated by underlying neurologic conditions or their treatments. The American Academy of Neurology (AAN) Women’s Neurology curriculum provides core competencies guiding neurologic care through the lens of sex and gender across the lifespan.
Neurologic care during pregnancy and menopause requires careful attention to the dynamic interplay between hormonal transitions, evolving evidence on diagnostic and treatment safety, and the lifelong neurologic risks associated with neurologic complications of pregnancy.
Despite the high prevalence of neurologic conditions in women, critical gaps remain in training, research, and clinical guidelines on sex- and gender-specific considerations across the lifespan.^1^ In 1977, the US Food and Drug Administration (FDA) recommended excluding all women of reproductive potential from phase 1 and phase 2 studies, which was not reversed by federal law until 1993. Today, more than 90% of FDA-approved medications have unknown teratogenic risks, and less than 1% of active World Health Organization–certified clinical trials include pregnant subjects.^2^ In response to these gaps, the American Academy of Neurology (AAN) published its first Women’s Neurology curriculum with defined competencies across key physiologic transitions, including pregnancy and menopause.^3^
Neurologists are often consulted to collaborate in the care of pregnant patients in two to evaluate new neurologic symptoms that arise during pregnancy or in the peripartum period, and to comanage patients with preexisting neurologic conditions in preconception counseling as well as during pregnancy and the peripartum period. Safeguarding the health of the pregnant individual remains paramount to optimizing fetal outcomes and is a guiding principle in the management of neurologic conditions during pregnancy.
However, caring for women with neurologic conditions extends beyond reproductive health. Menopause, whether arising naturally or induced by surgery or cancer treatment, brings about profound hormonal changes that can influence neurologic conditions and brain health, yet little is known about the neurology of menopause.
This article discusses the diagnosis and management of neurologic complications of pregnancy and menopause, as well as the care of individuals with preexisting neurologic conditions during these life stages. Although much of the data discussed in this article are derived from studies of cisgender women, the conditions described may affect individuals of any gender who experience pregnancy or menopause, including transgender men and nonbinary and intersex people, who are underrepresented in clinical research.
Choosing to become pregnant can be a complex decision for patients with chronic neurologic disorders. Careful preconception counseling is necessary to discuss appropriate management and ideally reach optimal disease control before pregnancy. Despite the growing array of neurologic therapies, data guiding pharmacologic and nonpharmacologic treatment of neurologic conditions during pregnancy remain limited. These gaps in safety data highlight the critical importance of optimizing neurologic care before pregnancy whenever possible and encouraging patients to enroll in pregnancy exposure registries. [KP 1] This section discusses management of neurologic conditions during higher-risk peripartum periods, starting at approximately 20 weeks gestation, intrapartum (labor and delivery), and postpartum (up to approximately 12 weeks after delivery). In 2015, the FDA replaced the letter-based pregnancy risk categorization with the narrative Pregnancy and Lactation Labeling Rule that includes a risk summary, clinical considerations, and a summary of data for use in pregnancy and lactation, as well as information on pregnancy, contraception, and infertility for females and males of reproductive potential. Drug label information that includes Pregnancy and Lactation Labeling Rule content is available through the online databases listed in the Useful Resources section at the end of this article.
CT and iodinated and gadolinium contrast agents pose potential risks to the developing fetus. The following discussion is based on American College of Obstetricians and Gynecologists (ACOG) and American College of Radiology (ACR) guidelines. If accessible promptly, noncontrast MRI is considered safer than CT during pregnancy in cases in which they are equivalent for the diagnosis in question. However, CT and iodinated contrast should not be withheld if they are clinically indicated or more readily available (eg, evaluation of acute ischemic stroke). [KP 2] Although the risks and benefits of both the imaging modality and contrast medium must be considered and discussed with pregnant patients, in general, if the results of an imaging study are felt to be critical to the treatment of the patient, potential risks of the radiologic study may need to be incurred.
Noncontrast MRI and ultrasonography are the imaging techniques of choice for pregnant patients and are preferable to imaging that uses ionizing radiation, such as CT and x-ray.^4^ [KP 3] There are no documented reports of MRI-induced teratogenesis or fetal acoustic injuries.
Gadolinium-based contrast agents are water soluble and can cross the placenta into the fetal circulation and amniotic fluid. A population-based retrospective cohort study of more than 1.4 million pregnancies found gadolinium-enhanced MRI was associated with an increased risk of fetal or neonatal death (adjusted risk difference 47.5 per 1000 pregnancies; 95% confidence interval [CI], 9.7 to 138.2), as well as rheumatologic, inflammatory, and infiltrative skin conditions in the fetus (adjusted risk difference 45.3 per 1000 person-years; 95% CI, 11.3 to 86.8).^4^ Gadolinium should generally be avoided and only used if the additional diagnostic yield provided is expected to improve maternal and fetal outcomes (eg, suspected abscess or malignancy affecting the brain or spinal cord).^5^ In pregnant patients with cerebrovascular conditions, noncontrast time-of-flight MR angiography (MRA) and MR venography (MRV) are recommended over gadolinium-enhanced MRA and MRV but are more susceptible to motion and flow-related artifacts (such as in distal vessels or aneurysms).^6^
The amount of radiation exposure from CT is generally not associated with fetal harm, particularly with imaging of the head and neck (ie, as opposed to the abdomen and pelvis). Although abdominal shielding was historically offered during CT examinations of the head or neck, the ACR now recommends against the use of abdominal shielding when the abdomen is outside the field of view because this may increase internal scatter and the radiation dose to the fetus.^7^ Although IV iodinated contrast media can cross the placenta and either enter the fetal circulation or pass directly into the amniotic fluid, animal studies have not demonstrated teratogenic or mutagenic effects from its use. Therefore, the ACR supports the use of IV iodinated contrast agents in pregnant patients when they are needed for diagnostic purposes. [KP 4]
The teratogenic risk of digital subtraction angiography is unknown because data are largely limited to case reports. As with any neurodiagnostic test, potential risks to the fetus may need to be incurred if the test is clinically indicated (eg, concern for aneurysm requiring acute intervention or mechanical thrombectomy for the treatment of ischemic stroke due to large vessel occlusion).^8^
Headache disorders are common in the general population, especially among women during their childbearing years. Pregnancy and postpartum are periods of increased risk for both exacerbation of primary headache disorders (eg, migraine) and development of new secondary headaches (eg, due to cerebral venous thrombosis). It is critical to determine whether headaches in a pregnant patient are primary, secondary, or both.
Sex hormones play a critical role in migraine pathophysiology. Decreasing estrogen levels during menstruation are associated with increased frequency of migraine without aura, whereas persistently elevated estrogen during pregnancy is generally associated with increased frequency of migraine with aura.^9^ Emerging data support an association between reductions in estrogen and increased release of the neuropeptide calcitonin gene-related peptide (CGRP), a key migraine trigger and target of several new migraine therapies. Sex hormones are also implicated in the heightened risk for secondary headache due to venous sinus thrombosis during this period.
As in any patient with headache, the history should evaluate for “red flags” suggestive of a secondary headache disorder, and the examination should evaluate for any focal signs or papilledema. Although pregnancy is sometimes classified as a red flag for secondary causes of headache, primary headache disorders are more common in pregnancy than secondary headache disorders. [KP 5] Factors that should raise particular concern for a secondary cause of headache in pregnancy and the peripartum period can be remembered by the peripartum mnemonic illustrated in Table 10-1.
Although most pregnant patients with primary headache disorders have received this diagnosis before pregnancy, migraine may start during pregnancy in up to 10% of pregnancies, most commonly during the first trimester.^10^ A new headache or change in a patient’s typical headache (eg, change in location, pattern, severity) that develops during pregnancy or the postpartum period warrants careful evaluation for secondary causes. Preeclampsia should be considered for any headache presentation in patients at more than 20 weeks gestation or postpartum and evaluated for by measuring blood pressure and urine protein. [KP 6] The highest risk period for cerebrovascular causes of headache, such as cerebral venous thrombosis, is late in the third trimester and especially early postpartum. [KP 7] If the patient undergoes epidural anesthesia during delivery, postdural puncture headache should be considered and evaluated for by assessing for orthostatic headache in the patient’s history. Considerations regarding neuroimaging in pregnant patients are discussed in the previous section; in general, neuroimaging should be obtained if needed for diagnosis because risks to the fetus are low, with a preference for MRI without contrast unless contrast is necessary to arrive at a diagnosis.
Migraine is among the most prevalent and disabling conditions worldwide, ranked third among nervous system disorders, and has the highest female-to-male ratio of any nervous system disorder (odds ratio [OR], 1.62; CI, 1.39 to 1.79).^11^ Migraine prevalence varies throughout a woman’s lifespan, with peak prevalence during reproductive age. A 2024 umbrella review of systematic reviews concluded that migraine was associated with an increased risk of preeclampsia and preterm birth (pooled OR, 2.05; 95% CI, 1.47 to 2.84 and OR, 1.26; 95% CI, 1.21 to 1.32, respectively).^12^ An analysis of 30,555 incident pregnancies in the Nurses’ Health Study II found individuals with migraine (versus without migraine) had a higher risk of preeclampsia (relative risk, 1.40; 95% CI, 1.19 to 1.65), and that those with migraine and regular prepregnancy aspirin use may have a lower risk of preterm delivery and preeclampsia.^13^ Although the US Preventive Services Task Force does not include migraine in its list of conditions warranting low-dose aspirin (81 mg a day) as a preventive medication for preeclampsia, the author’s practice is to consider low-dose aspirin after 12 weeks of gestation on a case-by-case basis for patients with migraine, particularly when additional risk factors for preeclampsia are present.^14^ Migraine is also associated with an increased risk of maternal ischemic stroke, with the highest risk observed among patients with migraine with aura (OR, 23.26; 95% CI, 18.46 to 29.31), followed by migraine without aura (OR, 8.15; 95% CI, 4.79 to 13.88); this elevated risk may be partly mediated by hypertensive disorders of pregnancy discussed in later sections of this article.^15^
Similar to migraine, tension-type headache predominantly affects women 15 to 49 years, although comparatively less is known about the role of sex hormones in this entity.^11^
Recognizing typical trajectories for headache symptoms during pregnancy can help guide management decisions. At least 60% of women with migraine report reductions in migraine frequency or severity during pregnancy, particularly patients with migraine without aura or menstrual migraine.^16^ [KP 8] Improvement by the end of the first trimester tends to predict continued improvement for the duration of pregnancy, allowing clinicians to take a more conservative approach to medication use. Addressing potential exacerbating factors such as inadequate hydration, suboptimal nutrition, irregular sleep, analgesic overuse, and psychosocial stressors is also important for headache management in pregnancy.
Table 10-2^17–19^ summarizes existing safety data and efficacy for abortive medications used in primary headache disorders. First-line abortive therapy in pregnancy is acetaminophen, followed by acetaminophen with caffeine, 200 mg or less, or by the combination of metoclopramide with diphenhydramine.^17^ [KP 9] ACOG and the American Academy of Pediatrics maintain that the preponderance of evidence fails to support a causal link between prenatal acetaminophen use and neurodevelopmental disorders.^20,21^ According to ACOG, second-line treatments include sumatriptan (the preferred triptan during pregnancy), IV magnesium, and nonsteroidal antiinflammatory drugs such as ibuprofen or ketorolac (these latter two only during the second trimester).^17^ Although aspirin is considered safe at lower doses (up to 150 mg), other nonsteroidal antiinflammatory drugs should be used sparingly and only during the second trimester because of the risk of adverse fetal effects during the first and third trimesters. Ergots are contraindicated during pregnancy because of the risk of inducing uterine contractions and vasospasm. For refractory migraine, a short course of prednisone or prednisolone can also be considered because they are inactivated by placental 11-β-hydroxysteroid dehydrogenase and so do not enter the fetal circulation; dexamethasone should be avoided because it is not inactivated. Peripheral occipital nerve blocks may also be effective.
Table 10-3 summarizes existing safety data for preventive medications used in primary headache disorders. Preferred preventive treatments for migraine in pregnancy include peripheral nerve blocks and onabotulinumtoxinA and oral medications such as calcium channel blockers, beta-blockers (eg, metoprolol, propranolol), and antidepressants (tricyclics or serotonin norepinephrine reuptake inhibitors [SNRIs]).^22^ Table 10-2 and Table 10-3 also provide examples of nonpharmacologic and alternative management strategies, which should always take patient-specific comorbidities and drug interactions into consideration.
In addition to its role in migraine pathophysiology and treatment, CGRP also plays a role in reproductive physiology. CGRP regulates uteroplacental blood flow to support fetal development, with circulating levels increasing during pregnancy and then decreasing sharply at term and postpartum. Lower CGRP levels have been observed in patients with preeclampsia and intrauterine growth restriction. The latest safety analyses of CGRP antagonist monoclonal antibodies using the World Health Organization pharmacovigilance database across 286 safety reports found no signal of increased reporting of spontaneous abortion compared with the entire database or a specific pattern of fetal-maternal toxicity.^23^ However, long-term data on the safety of CGRP antagonists during pregnancy are not presently available; therefore, the current recommendation is that CGRP monoclonal antibodies should be stopped 5 to 6 months before planned conception, and gepants should be stopped 5 to 7 days before planned conception.^17^ [KP 10]
Secondary headache is diagnosed in approximately one-third of pregnant women for whom neurologists are consulted for acute headache.^24^ A general approach to diagnosing secondary headache is discussed previously and summarized in Table 10-4. The three secondary headache categories defined by the International Classification of Headache Disorders, Third Edition, that are most commonly encountered during pregnancy and postpartum are headaches attributed to (1) nonvascular intracranial disorders (eg, idiopathic intracranial hypertension, postdural puncture headache), (2) trauma to the head or neck, and (3) cerebrovascular disorders.
The effect of pregnancy on the course of idiopathic intracranial hypertension was explored in a prospective study of 377 women with confirmed idiopathic intracranial hypertension divided into four groups by timing of their idiopathic intracranial hypertension diagnosis (prepregnancy, during pregnancy, after pregnancy, or without ever becoming pregnant).^25^ Idiopathic intracranial hypertension was diagnosed during pregnancy in 2% of subjects, which was associated with greater papilledema but similar vision metrics compared with subjects with established idiopathic intracranial hypertension who became pregnant.^25^ Pregnancy did not adversely affect visual or headache outcomes over time, with trajectories similar to idiopathic intracranial hypertension subjects without a history of pregnancy.^25^ These findings differ from a subsequent but smaller prospective cohort of 42 pregnant patients with idiopathic intracranial hypertension in which worsening of idiopathic intracranial hypertension–related symptoms occurred in 18 subjects (49%), mostly occurring transiently during the first and second trimesters and without need for escalation of treatment;^26^ only two patients experienced recurrence of papilledema.
Pharmacologic options for idiopathic intracranial hypertension management during pregnancy are limited because the carbonic anhydrase inhibitors topiramate and zonisamide are teratogenic and should generally be avoided, although the use of acetazolamide is controversial because one small study found no increase in adverse events.^27^ Therefore, achieving disease control before conception is critical. Avoidance of excessive gestational weight gain is important because of the risk of idiopathic intracranial hypertension exacerbation. If idiopathic intracranial hypertension is active with imminent risk of vision loss, then lumbar puncture, serial lumbar punctures, or lumbar drain may be pursued to temporize symptoms before considering sight-saving surgery as a last resort, which can include optic nerve sheath fenestration or shunt (ventriculoperitoneal or lumboperitoneal).^27^ No specific mode of delivery is recommended for patients with idiopathic intracranial hypertension; therefore, this should be decided by obstetric factors only, except in cases of severe papilledema with rapidly declining vision, for which caesarean delivery may be preferred to limit use of the Valsalva maneuver.^27^ [KP 11] Spinal or epidural anesthesia can be given if needed.
Epidural analgesia is used in approximately 75% of US pregnancies, and postdural puncture headache is its most common complication. Postdural puncture headache is a headache attributed to CSF leak and low CSF pressure that typically occurs within 5 days of dural puncture and tends to improve when the patient is supine.^28^ The dural puncture leading to postdural puncture headache may be caused by epidural anesthesia (unintentional dural puncture) or spinal anesthesia (intentional dural puncture). Noncutting needles and narrower-gauge needles are associated with decreased postdural puncture headache risk.^28^ Other complications of intracranial hypotension include cranial nerve dysfunction, subdural hematoma, and cerebral venous thrombosis. Additional complications of neuraxial anesthesia are discussed later in this article.
Conservative initial management of postdural puncture headache includes oral hydration, analgesia (eg, acetaminophen and nonsteroidal antiinflammatory drugs), and caffeine (maximum dose of 900 mg a day, or 300 mg a day if breastfeeding).^28^ If postdural puncture headache is refractory to conservative management, then an epidural blood patch should be considered, with greater success if it is performed at least 48 hours after the dural puncture. [KP 12]
Pregnant individuals with head injuries should be screened for intimate partner violence because this is a leading cause of head injury during pregnancy.^29^ [KP 13] Intimate partner violence affects one-fourth of women globally, and homicide is the leading cause of death during pregnancy and the postpartum period in the United States.^30^ [KP 14] A cross-sectional study using data from the National Violent Death Reporting System found that pregnancy-associated homicide rates were higher in states in which divorce could not be finalized during pregnancy compared with the rates in states without this barrier (incidence rate ratio, 2.11; 95% CI, 1.09 to 4.08).^31^ Approximately 6% of US women reported intimate partner violence during pregnancy.^30^ Although much of the literature on traumatic brain injury during pregnancy focuses on patients requiring hospitalization, these data likely underestimate the impact of mild traumatic brain injury and postconcussive syndrome, which often go undiagnosed or untreated. Strangulation may lead to dissection and stroke, and intimate partner violence increases the long-term risk of cerebrovascular disease (discussed in the next section). [KP 15] Women exposed to intimate partner violence during pregnancy are more likely than women who are not exposed to intimate partner violence during pregnancy to experience adverse birth outcomes such as preterm birth and low birth weight.^32^
Although pregnancy-related stroke is rare, its incidence of 30 per 100,000 pregnancies is approximately three times higher than the incidence of stroke in nonpregnant women of similar age, and it is increasing over time.^33^ [KP 16] The majority of ischemic and hemorrhagic strokes occur in the third trimester (close to the time of delivery) and postpartum period (especially the first 2 weeks). Risk factors for pregnancy-related stroke include cardiovascular disease (eg, hypertension, diabetes, tobacco use) and pregnancy-associated conditions (eg, hypercoagulable state, hypertensive disorders of pregnancy). Patients with a preexisting history of stroke may also become pregnant; therefore, controlling cerebrovascular risk factors is essential for both secondary stroke prevention and to reduce the risk of hypertensive disorders of pregnancy, such as preeclampsia.^34^
Physiologic changes associated with pregnancy and pregnancy-associated complications such as preeclampsia and eclampsia contribute to the heightened risk of both ischemic and hemorrhagic stroke. Pregnancy is associated with an increased risk of thrombosis due to Virchow hypercoagulable state (pregnancy is a prothrombotic state to prevent excessive bleeding during labor and delivery), venous stasis (due to the gravid uterus compressing venous structures and progesterone-mediated venous distensibility and capacitance), and endothelial injury (in the setting of delivery). Indeed, venous thrombosis is a leading cause of maternal morbidity and mortality, and the risk of venous thrombosis is increased by fivefold during pregnancy and sixtyfold during the first 12 weeks postpartum.^35^ [KP 17] Abnormalities in the early development of placental vasculature may lead to relative underperfusion and release of antiangiogenic factors that alter maternal systemic endothelial function, eventually leading to hypertensive disorders of pregnancy such as preeclampsia and related complications such as vasoconstriction and microemboli, which all contribute to cerebrovascular risk.
Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal mortality and complicate as many as 8% of pregnancies worldwide.^34^ In pregnancy, hypertension is defined as systolic blood pressure of 140 mm Hg or greater, diastolic blood pressure of 90 mm Hg or greater, or both. When hypertension in pregnancy leads to end organ dysfunction, this is referred to as preeclampsia. More severe manifestations of preeclampsia include eclampsia (preeclampsia complicated by seizures or coma) and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome.
Hypertensive disorders of pregnancy are associated with both neurologic complications during pregnancy and with an increased long-term risk of stroke and cardiovascular disease later in life.^36,37^ Preeclampsia is associated with a threefold increased risk of hypertension and an approximately twofold increased risk of stroke and heart disease compared with patients without preeclampsia.^38^ American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend screening for hypertensive disorders of pregnancy and identifying and treating modifiable stroke risk factors (especially hypertension) in these patients.^39^ [KP 18]
Racial, ethnic, and socioeconomic disparities are well documented in adverse pregnancy outcomes.^40^ [KP 19] These disparities may be in part due to structural, institutional, and systemic factors leading to differences in access to prenatal care. Compared with non-Hispanic White women, non-Hispanic Black women experience increased rates of hypertensive disorders of pregnancy, gestational diabetes, preterm delivery or having a low-birth-weight infant, and greater pregnancy-related mortality, including from preeclampsia, in which the case fatality rate is 2.7 times higher in Black women than in White women (73.5 versus 27.4 deaths per 100,000 cases).^40,41^
Blood pressure should be checked at every clinical encounter to screen for hypertensive disorders of pregnancy in pregnant patients, including outpatient neurology appointments. Although preeclampsia is traditionally defined as the combination of hypertension and proteinuria, preeclampsia can be diagnosed in patients with new-onset hypertension without proteinuria if they have features of severe disease, such as new neurologic symptoms.
Management of preeclampsia involves treatment of hypertension and prompt determination of the presence and severity of end organ involvement (ie, encephalopathy, new visual disturbance, or headache) followed by targeted treatment. Preeclampsia can occur postpartum, even after an uncomplicated pregnancy. Antihypertensive therapy is required for treatment of severe hypertension (systolic blood pressure of 160 mm Hg or greater, diastolic blood pressure of 110 mm Hg or greater, or both, measured twice, 15 minutes apart). However, blood pressure control does not alter the course of the disease nor prevent eclampsia.^39^ IV nicardipine is generally preferred for short-term antihypertensive therapy, with labetalol as an alternative.
Magnesium sulfate is the drug of choice to prevent eclampsia and prevent recurrent seizures in eclampsia, shown in randomized trials to be more effective than phenytoin and diazepam.^42^ [KP 20] Magnesium sulfate should therefore be given to women with severe features unless contraindicated (eg, myasthenia gravis). There is currently no consensus regarding prophylactic use of magnesium sulfate for the prevention of eclampsia in women with preeclampsia without severe features, nor is there consensus on the recommended dosage. Typical regimens include magnesium sulfate 4-g to 6-g IV loading dose (administered over 20 to 30 minutes) intrapartum, followed by a maintenance dose of 1g to 2 g/h until approximately 24 hours after delivery, monitoring for signs of toxicity such as decreased urine output, tachypnea, and absent patellar reflexes, and trending serum levels as indicated.^34^ If seizures occur (eclampsia), additional magnesium sulfate should be administered at a dose of 2 g to 4 g, intravenously. If status epilepticus occurs, IV or IM benzodiazepine should be administered. Seizures refractory to magnesium and benzodiazepines would be atypical for eclampsia and should trigger evaluation for additional provoking factors such as venous sinus thrombosis or intracranial hemorrhage. [KP 21]
Preeclampsia and eclampsia may be complicated by PRES, which is characterized by vasogenic edema that preferentially affects the parietal and occipital lobes. In one study of 47 patients with eclampsia and head imaging, 46 of these patients (98%) had evidence of PRES.^43^ Management of PRES in the context of preeclampsia or eclampsia is described previously, including treatment of hypertension, administration of magnesium sulfate, and delivery if PRES occurs in the antepartum period.
Reversible cerebral vasoconstriction syndrome is more likely to occur postpartum than antepartum. Complications include ischemic stroke, vasogenic edema, and nonaneurysmal subarachnoid hemorrhage, although initial neuroimaging (CT, MRI) may be normal in up to one-third of patients. Pharmacologic risk factors in the postpartum period include recent initiation or uptitration of selective serotonin reuptake inhibitors (SSRIs) for postpartum depression or triptan use for migraine. [KP 22] Management of reversible cerebral vasoconstriction syndrome involves symptomatic treatment of headache (calcium channel blockers may be helpful; avoid triptans), management of seizures if they occur, discontinuation of potential culprit medications, and management of preeclampsia and eclampsia.
Causes of ischemic stroke during pregnancy and the peripartum period include preeclampsia and eclampsia, PRES, reversible cerebral vasoconstriction syndrome, embolism (eg, cardiac, amniotic fluid), pregnancy-associated hypercoagulability, and cervical artery dissection. If an acute stroke is suspected, the most readily available imaging modality (CT or MRI) should be used because the benefits of timely diagnosis and treatment outweigh any potential (and low) risks of the imaging modality. [KP 23] Although pregnant patients have been excluded from acute ischemic stroke therapy trials, AHA/ASA guidelines recommend that IV alteplase be considered in pregnancy when the anticipated benefit of treating moderate or severe stroke outweigh the increased risk of uterine bleeding; therefore, this determination should be made on a case-by-case basis in consultation with an obstetric team.^44^ [KP 24] Less is known about tenecteplase in pregnancy; therefore, administration of this medication warrants a similar risk-benefit discussion as alteplase. Both alteplase and tenecteplase are large molecules that do not cross the placenta and, in animal studies, are not teratogenic at doses used to treat acute ischemic stroke. A population-based cross-sectional analysis using national claims data found that mechanical thrombectomy was both safe and effective in pregnant and postpartum patients, with no patients who underwent thrombectomy experiencing miscarriage.^45^
Low-dose aspirin can be safely used for secondary stroke prevention during pregnancy, although doses above 150 mg are not recommended after 28 weeks gestation because of the potential for premature closure of the fetal ductus arteriosus. Considerations related to anticoagulation in pregnancy are discussed in the section Cerebral Venous Thrombosis.
Amniotic fluid embolism is a rare condition with a mortality rate of up to 50%.^46^ Amniotic fluid embolism is somewhat of a misnomer because it is likely not due to amniotic fluid nor embolism; rather, amniotic fluid embolism is thought to be triggered by fetal tissue and antigens entering the maternal circulation, leading to a proinflammatory response similar to systemic inflammatory response syndrome.^46^ Amniotic fluid embolism is characterized by sudden cardiorespiratory arrest or hypotension with respiratory compromise and disseminated intravascular coagulopathy, with onset during labor or within 30 minutes of placental delivery, and is the most common cause of peripartum cardiac arrest (Case 10–1).^47^ [KP 25] Patients may experience neurologic symptoms such as encephalopathy and seizure, although this is not part of the diagnostic criteria. Management of amniotic fluid embolism includes basic and advanced cardiac life support, treatment of disseminated intravascular coagulopathy and hemorrhage with blood product transfusions and tranexamic acid, and determination of the need for immediate delivery.^46^
A 34-year-old woman, gravida 3, para 2, with an uncomplicated pregnancy presented in active labor at 39 weeks gestation and underwent vaginal delivery of a healthy baby boy. Within a few minutes of delivery, she became acutely encephalopathic, followed by the development of hypotension, bradycardia, and hypoxia. She developed profuse uterine bleeding, indicating likely disseminated intravascular coagulation and raising concern for amniotic fluid embolism. A code blue and massive transfusion protocol were activated. She was intubated and briefly lost pulses, and cardiopulmonary resuscitation was initiated. Following the return of spontaneous circulation, she did not follow commands or respond to voices, but she did have symmetric pupillary responses and moved her limbs within the plane of the bed. Targeted temperature management was recommended for neuroprotection, which she tolerated.
A head CT was unremarkable. Systemic imaging revealed innumerable thromboses, including pulmonary emboli, for which heparin was initiated. A brain MRI demonstrated multifocal punctate infarcts, predominantly posterior and infratentorial, with patent anterior and posterior circulation on MR angiography (Figure 10-1). A transthoracic echocardiogram estimated an ejection fraction of 25% to 30% without intracardiac shunt, raising concern for a cardioembolic source of stroke, although a pulmonary shunt was not excluded.
Two days later, she was alert and followed commands, and she was extubated without focal neurologic deficits.
This case highlights the importance of early recognition and rapid multidisciplinary management of amniotic fluid embolism. The patient’s acute encephalopathy, cardiorespiratory collapse, and coagulopathy were important clues for amniotic fluid embolism. Prompt supportive critical care and targeted temperature management for neuroprotection in the event of cardiac arrest may help mitigate the harm from this rare and often catastrophic obstetric emergency.
[end case]
Cerebral venous thrombosis most commonly occurs late in pregnancy or in the postpartum period in association with hypercoagulability during this period. Risk factors for cerebral venous thrombosis in pregnancy include dehydration, older maternal age, cesarean delivery, underlying thrombophilia, obesity, polycystic ovary syndrome, and COVID-19 infection (Case 10–2).^48^
A 37-year-old woman, gravida 2, para 1, with gestational diabetes presented in labor at 38 weeks gestation. Her blood pressure was 185/90 mm Hg and 163/85 mm Hg on repeat testing. She reported no vision changes or headache. She was diagnosed with preeclampsia with severe features. Labor was induced, and she was treated with antihypertensives and had vaginal delivery without further complications. She received IV magnesium sulfate, and she remained normotensive through discharge.
One week later, she presented to the emergency department as a code stroke for a new headache and left-sided weakness. A head CT revealed a large right frontal intraparenchymal hemorrhage with 7 mm leftward midline shift. Delayed postcontrast imaging showed a right frontal cortical vein thrombosis that was confirmed on a brain MRI and MR venography (MRV), which also revealed partial anterior superior sagittal sinus thrombosis. She was started on IV heparin.
This case illustrates the delayed onset of cerebral venous sinus thrombosis with intracerebral hemorrhage in the postpartum period following preeclampsia with severe features. Although the patient’s hypertensive disorder resolved with standard obstetric management, her subsequent neurologic symptoms highlight the importance of maintaining vigilance for postpartum cerebrovascular complications, even in patients who appear clinically stable at discharge. Cerebral venous sinus thrombosis is a rare but serious cause of postpartum stroke, often presenting with headache and focal deficits. Despite the presence of hemorrhage, anticoagulation remains the mainstay of treatment. This case underscores the need for multidisciplinary follow-up and patient education on warning signs of neurologic complications in the postpartum period.
[end case]
The preferred anticoagulant during pregnancy is low-molecular-weight heparin; vitamin K antagonists such as warfarin are teratogenic and contraindicated during pregnancy, and direct oral anticoagulants should be avoided due to a lack of sufficient safety data.^6^ [KP 26] Pregnancy is not a contraindication for endovascular therapy or decompressive hemicraniectomy if the patient’s condition deteriorates despite anticoagulation, although current guidelines do not comment specifically on assessing risks and benefits of these interventions in pregnant patients.^6^ As in patients who are not pregnant, the duration of anticoagulation is determined by whether an underlying hypercoagulable state is identified outside of the temporary hypercoagulable state of pregnancy, with anticoagulation continued for approximately 6 months if no alternative etiology is found. Patients with a history of venous thromboembolism have an increased risk of thrombotic events during future pregnancies. Cerebral venous thrombosis is not a contraindication to future pregnancy, and patients who receive prophylactic anticoagulation during pregnancy appear to have lower rates of recurrence.^49^
A 2024 retrospective study of 134 adults (peripartum women, nonpregnant women, and men) with nontraumatic intracerebral hemorrhage found that one in five cases were related to pregnancy, with 60% of these cases occurring postpartum, often in association with reversible cerebral vasoconstriction syndrome.^50^ Intracerebral hemorrhage during pregnancy and the postpartum period is primarily associated with hypertensive disorders of pregnancy, and intracerebral hemorrhage is the cause of death in approximately one-third of preeclampsia-associated deaths.^51^ Additional risk factors for intracerebral hemorrhage in pregnancy include advanced maternal age, cardiac disease, and smoking.
A large population-based Finnish study reported a pregnancy-related subarachnoid hemorrhage incidence of 3.2 cases per 100,000 deliveries, with 77% due to ruptured aneurysm, which also conferred a greater risk of mortality compared with nonaneurysmal subarachnoid hemorrhage.^52^ Although physiologic factors such as increased cardiac output and arterial remodeling may increase the risk of rupture for vascular malformations such as intracranial aneurysms, studies conflict on whether pregnancy itself increases this risk.^53^
As in nonpregnant patients, acute management of hemorrhagic stroke focuses on lowering blood pressure, correcting coagulopathies, and treating the underlying etiology. Fetal monitoring should be used to evaluate for signs of placental hypoperfusion. If intracerebral hemorrhage occurs in the setting of preeclampsia, magnesium sulfate is the standard therapy for seizure prevention. For pregnant patients with hemorrhagic stroke due to rupture of a vascular lesion, endovascular or surgical intervention should be pursued based on best clinical practice and not delayed due to pregnancy. Although rare, metastatic choriocarcinoma should be considered if a patient develops multifocal hemorrhagic brain lesions in the postpartum period.
Pituitary apoplexy is a rare, potentially life-threatening condition caused by infarction, hemorrhage, or both in the pituitary gland. Although pituitary apoplexy typically occurs in the context of a preexisting pituitary mass (eg, pituitary adenoma), it can occur in pregnancy in the absence of a lesion due to physiologic pituitary hyperplasia leading to an expansion up to 136% its usual size.^54^ CT is often insensitive for the diagnosis of pituitary apoplexy unless hemorrhage is present; therefore, MRI is preferred when available. If surgery is required based on the severity of symptoms, pregnancy is not a contraindication.^55^
The 2020 AHA resuscitation guidelines provide a framework for optimization of the resuscitation of patients who experience cardiac arrest during pregnancy.^56^ The guidelines note that there are no randomized trials that study the use of targeted temperature management in pregnancy, but they cite case reports of good maternal and fetal outcomes with targeted temperature management, and therefore recommend targeted temperature management for pregnant women who remain comatose after resuscitation from cardiac arrest if there are no other contraindications; continuous fetal monitoring for bradycardia is recommended during targeted temperature management.^56^ [KP 27]
Although most pregnancies in women with epilepsy are uncomplicated, there is growing recognition that women with epilepsy are at increased risk of complications such as gestational hypertension, preeclampsia, and preterm birth compared with women without epilepsy.^57^ [KP 28] In a recent multinational study of 4,511,267 deliveries (including 35,283 in women with epilepsy), the rate of composite severe maternal morbidity and mortality was higher in women with epilepsy compared with those without epilepsy (36.9 versus 25.4 per 1000 deliveries).^58^
Preconception management is critical to ensure success with an antiseizure medication regimen that optimizes both seizure control and fetal outcomes. Seizure freedom for at least 9 months before pregnancy is associated with up to a 92% rate of remaining seizure free during pregnancy.^59^ Based on available registry data, lamotrigine, levetiracetam, and oxcarbazepine monotherapy are associated with the lowest birth prevalence of any major congenital malformations, whereas valproic acid is associated with the highest risk as well as worse neurodevelopmental outcomes.^60^ [KP 29] However, once a patient is pregnant, updated practice guidelines from the AAN, American Epilepsy Society, and Society for Maternal-Fetal Medicine jointly recommend exercising caution in attempting to remove or replace suboptimal antiseizure medications (including valproic acid) if they are effective in controlling convulsive seizures. This is because neurulation has typically already occurred, and such antiseizure medication changes are associated with a doubling of the risk of generalized seizures during pregnancy.^60^ These practice guidelines also recommend prescribing at least 0.4 mg of folic acid orally to reduce the risk of neural tube defects; however, there are no data to support optimal folic acid dosing, and prescribing practices vary.^60^ Neuromodulation devices are likely safe during pregnancy.
Antiseizure medication dose adjustment is often needed during pregnancy because of expected physiologic changes, such as increased renal clearance, hepatic metabolism, and volume of distribution, as well as decreased medication absorption in hyperemesis gravidarum. For example, concentrations of lamotrigine, levetiracetam, oxcarbazepine, lacosamide, and zonisamide decrease during pregnancy.^61^ Preconception drug levels during a period of good seizure control should be obtained, and monthly monitoring of drug levels during pregnancy and postpartum should be performed with dosage modification to maintain therapeutic levels. [KP 30]
In women with epilepsy, seizures during pregnancy are most commonly caused by subtherapeutic antiseizure medications, but pregnancy-associated conditions should also be considered, such as eclampsia, PRES, reversible cerebral vasoconstriction syndrome, and cerebral venous thrombosis. Additionally, patients should be evaluated for common triggers of seizures, such as infection and metabolic disturbance.
Eclampsia-associated seizures should be treated with magnesium sulfate. Pregnant patients were excluded from randomized clinical trials comparing antiseizure medication efficacy during status epilepticus. IV or intramuscular benzodiazepine, followed by an IV load of either levetiracetam or fosphenytoin, is generally recommended for status epilepticus in pregnancy as it is in nonpregnant patients; valproic acid should generally be avoided because of its teratogenic potential, especially in the first trimester. Commonly used anesthetics, including propofol, are not associated with adverse fetal defects.
Pregnancy generally reduces rates of multiple sclerosis relapse, except in patients discontinuing natalizumab or sphingosine-1-phosphate receptor modulators who face an increased risk of rebound relapse.^62^ In contrast, pregnancy is associated with an increased risk of neuromyelitis optica spectrum disorder (NMOSD) relapse, and NMOSD is also associated with obstetric complications such as miscarriage and preeclampsia, attributed to aquaporin-4 (AQP4) expression in the placenta, leading to anti-AQP4 IgG–triggered inflammation.^63^ [KP 31]
Treatment of an acute multiple sclerosis relapse during pregnancy can be considered if symptoms are disabling (Table 10-5^64,65^). Short courses of glucocorticoids are classified as low risk during pregnancy by ACOG.^66^ Methylprednisolone, prednisolone, and prednisone are preferred because they are inactivated by placental 11-β-hydroxysteroid dehydrogenase and therefore do not enter the fetal circulation; dexamethasone should be avoided because it is not inactivated.^66^ [KP 32] However, controversy remains about the use of glucocorticoids during the first trimester because of concerns about increased risk of craniofacial and urogenital abnormalities.^67^ The first consensus recommendations for NMOSD in pregnant patients were published by the French Multiple Sclerosis Society in 2023, which similarly recommend treating intrapartum relapses with short-course high-dose methylprednisolone followed by plasma exchange for severe relapses that do not respond to steroids.^63^
Guidance for the acute management of autoimmune encephalitis during pregnancy is largely limited to systematic reviews of case series. First-line therapies during pregnancy include glucocorticoids, plasma exchange, and IV immunoglobulin (IVIg); use of second-line immunomodulatory therapies (eg, rituximab) should be discussed on an individual patient basis.^68^ [KP 33]
Disease-modifying therapies for multiple sclerosis are typically discontinued before pregnancy, but some patients at high risk may elect to continue medications (eg, natalizumab, glatiramer acetate). A 2025 study of pregnancy outcomes from 3244 women with multiple sclerosis who received ocrelizumab (1071 with intrauterine exposure) found no associated increased risk of adverse pregnancy or infant outcomes.^69^ Drawing from case series of pregnant patients with paroxysmal nocturnal hemoglobinuria, eculizumab appears to be safe during pregnancy, and its use may be considered in pregnant patients with NMOSD.^70^ Noncontrast MRI can be performed if needed to guide treatment decisions, but gadolinium should be avoided during pregnancy.
Preexisting neuromuscular conditions may require specific management during pregnancy, and new neuromuscular complications may occur in the peripartum period.
The course of myasthenia gravis during pregnancy is variable, but if exacerbations occur, they are more likely in the first trimester and postpartum.^71^ Oral pyridostigmine is safe during pregnancy but may require dose adjustment in later trimesters because of changes in volume of distribution and renal clearance. [KP 34] However, IV acetylcholinesterase inhibitors may produce uterine contractions and should not be used until labor, when this route may be preferred because of the risk of abnormal gastrointestinal motility and absorption with oral medications. Prednisone may also be used during pregnancy; azathioprine and cyclosporine can be considered, but they have been linked to preterm labor and intrauterine growth restriction at higher doses.^66^ Drawing from case series of pregnant patients with paroxysmal nocturnal hemoglobinuria, eculizumab appears to be safe during pregnancy. Plasma exchange and IVIg have been safely used to treat myasthenic crisis in pregnancy.
In patients with myasthenia gravis who develop preeclampsia or eclampsia, magnesium sulfate is contraindicated because it may precipitate myasthenic crisis; instead, alternative antiseizure medications (eg, levetiracetam) can be used. [KP 35]
Early anesthesiology consultation is recommended for pregnant patients with myasthenia gravis. Neuraxial analgesia is recommended in patients with mild-moderate disease when vaginal delivery is anticipated, which will allow for an assisted second stage in the event of fatigue. General anesthesia is recommended for cesarean delivery in patients with significant bulbar or respiratory weakness because intraoperative neuraxial anesthesia (midthoracic level or higher) may lead to respiratory compromise. Neuromuscular blocking agents should be avoided, when possible, especially if the reversal agent sugammadex is not available.
Nerve injuries occur in up to 2% of vaginal births, most commonly affecting the femoral nerve and the lateral femoral cutaneous nerve.^72^ [KP 36] Risk factors include a prolonged second stage of labor, instrumental delivery, nulliparity, large fetus, and, less commonly, intraoperative positioning or retractor positioning during cesarean delivery.^72^ Carpal tunnel syndrome, femoral neuropathy, and lateral femoral cutaneous neuropathy (meralgia paresthetica) are the most common mononeuropathies during pregnancy due to fluid retention and mechanical compression.
Neurologists are often consulted regarding the planning for delivery in patients with neurologic conditions. Such decisions should involve a multidisciplinary team, including obstetricians, anesthesiologists, and neurologists.
For patients with neurologic conditions sensitive to increased intracranial pressure (eg, idiopathic intracranial hypertension), neurologists are often consulted on whether vaginal delivery with pushing (Valsalva maneuver) is safe or if an assisted second stage of vaginal delivery or cesarean delivery should be pursued. Neurologists are also consulted on the safety of neuraxial anesthesia (versus general anesthesia) because of the potential risk of increased intracranial pressure with an epidural injection or risk of a change in CSF gradient with accidental dural puncture. Although current data on the safety of vaginal versus cesarean delivery in patients with neurologic conditions are mostly based on retrospective case series, very few neurologic conditions seem to warrant cesarean delivery (which is associated with an increased risk of adverse maternal outcomes compared with vaginal delivery in the general population). Valsalva maneuver or neuraxial anesthesia is associated with an increased risk of herniation in patients with evidence of increased intracranial pressure from a space-occupying lesion with mass effect or obstruction of CSF flow at or above the foramen magnum, in which case cesarean delivery with general anesthesia is advised.^73^ In contrast, transient increases in intracranial pressure during vaginal delivery have not been shown to be harmful in patients with stable idiopathic intracranial hypertension (ie, absence of severe papilledema with rapidly declining vision). As a general principle, the author recommends avoiding vaginal delivery in any patient in whom lumbar puncture would be considered unsafe.
Unruptured intracranial aneurysms have historically been considered an absolute contraindication to vaginal delivery, but several studies have not found higher rates of rupture with vaginal delivery, leading some experts to recommend basing the mode of delivery on obstetric indications.^74^ There is no contraindication to vaginal delivery in patients with prior intracranial hemorrhage that was treated (eg, clipping or embolization of an aneurysm or arteriovenous malformation).^73^
The most common complication of obstetric epidural and spinal anesthesia is postdural puncture headache, discussed previously. Rare complications include epidural hematoma (in patients on antithrombotic medications or with coagulopathy [eg, due to HELLP syndrome]), meningitis (typically occurring after dural puncture), epidural abscess (more likely to occur after prolonged epidural catheterization), and anesthetic toxicity. High or total spinal anesthesia is a rare complication of spinal or epidural anesthesia due to local anesthetic either entering the subdural or subarachnoid space, or an overdose of epidural anesthetic.^75^ This can present with rapidly ascending weakness and numbness that can lead to paralysis of the phrenic nerve, leading to respiratory depression, cardiac collapse, and coma due to the anesthetic extending to the brainstem. Management involves elevating the head of the bed to prevent further cephalad spread of the anesthetic, cardiovascular and respiratory support, and emergent delivery if there is evidence of fetal distress.
Local anesthetic systemic toxicity is due to systemic absorption of the local anesthetic that can lead to neurologic symptoms (from metallic taste, perioral paresthesias, and tinnitus to encephalopathy and seizures) and cardiovascular symptoms, including hypotension, arrhythmia, and cardiac arrest. Treatment requires rapid identification of this complication and administration of an IV lipid emulsion.^76^
Emergency contraception refers to contraceptive options that can decrease the risk of becoming pregnant. The primary consideration for patients with neurologic conditions requesting emergency contraception is drug-drug interactions. For example, if a patient used an enzyme-inducing drug (eg, phenytoin) within 4 weeks, then the dose of levonorgestrel (used in many over-the-counter emergency contraception pills) may need to be double the standard dose. [KP 37] For this reason, placement of a copper intrauterine device may be considered.
Pregnancy may be terminated with the use of oral medications or procedures (uterine aspiration or dilation and evacuation). Limited published data are available to guide recommendations for navigating abortion in patients with preexisting neurologic disorders, which requires careful consideration of medication interactions and whether in-hospital observation is warranted. Patients on anticoagulation require counseling about the indications for their medication and whether it is safe to temporarily stop therapy before an abortion. Because of the risk of bleeding complications, anticoagulation is a contraindication to mifepristone, and hospital-based abortion care may be preferred in these cases; therefore, closer monitoring and intervention are available. Patients taking enzyme-inducing antiseizure medications may require an increased dose of mifepristone before an abortion. [KP 38] In addition to its antiprogesterone action, mifepristone also competitively blocks glucocorticoid receptors, and caution is recommended in patients requiring corticosteroids for the treatment of immune-mediated neurologic conditions. Patients with spinal cord injury above the level of T6 may experience autonomic dysreflexia triggered by uterine contractions and likely benefit from in-hospital abortion and use of spinal or epidural analgesia regardless of the presence or absence of sensation.
Perimenopause is a transitional period that extends from the onset of menstrual cycle irregularities until 12 months after the final menstrual period, at which point menopause is confirmed. Perimenopause is due to a gradual decrease in ovarian function, and resultant increasing hormonal variability can lead to new neurologic symptoms or affect preexisting neurologic disorders. Spontaneous (natural) menopause is confirmed retrospectively by the cessation of menses for 12 months and occurs at a median age of 51 years in the United States. In contrast, induced menopause occurs when medical treatments or procedures (eg, chemotherapy, bilateral oophorectomy) affect ovarian function, leading to abrupt alterations in circulating hormones.^77^ Induced menopause and earlier age of onset of menopause (before age 45 years) may negatively affect neurologic health outcomes.
The clinical manifestations and severity of perimenopause symptoms demonstrate substantial variability across individuals and include vasomotor symptoms (eg, hot flushes, night sweats), sleep disturbances, and changes in cognition or mood. Management may include medications, such as hormone therapy or nonhormonal therapy (eg, fezolinetant, SNRIs), as well as nonpharmacologic options (eg, cognitive behavioral therapy). Hormone therapy is FDA approved for the treatment of vasomotor symptoms, osteoporosis prevention, and genitourinary syndrome of menopause (conditions that may be exacerbated by medications commonly prescribed by neurologists). The current understanding of how hormone therapy impacts neurologic conditions (or their treatments) is limited because of advances in hormone therapy formulations, dosing, administration routes, and initiation timing not represented in older studies discussed below.
Approximately one-half of female patients with migraine report a link between migraine and their menstrual cycle. Those with hormonally sensitive migraine (eg, menstrual migraine) often report an initial worsening during perimenopause (likely due to erratic estrogen fluctuations that may cause spikes in CGRP) and a subsequent improvement after the final menstrual period, when hormone levels stabilize. [KP 39] Migraine without aura tends to improve after menopause, whereas migraine with aura may persist.^78^ Tension-type headache may also become more frequent during perimenopause due to sleep disturbances, mood changes, and medication overuse.
CGRP is a potent vasodilator and increases during vasomotor symptom episodes. One cross-sectional study of more than 5000 women age 45 to 60 years found that women with migraine were more likely to report severe or very severe vasomotor symptoms versus no vasomotor symptoms compared with women without migraine (OR, 1.34; 95% CI, 1.08 to 1.66).^79^ Postmenopausal women on stable estrogen-containing hormone therapy have higher CGRP levels compared with untreated postmenopausal women but often report improved migraine and vasomotor symptoms control, likely because of achieving stable steady-state CGRP levels as opposed to episodic spikes. Although migraine frequency tends to improve in the postmenopausal period, patients with induced menopause tend to report worsening migraine, likely due to the abrupt and marked decrease in serum estradiol levels. [KP 40]
Migraine management during perimenopause involves standard therapies, such as CGRP antagonists and strategies targeting hormonal fluctuations. Although biologically plausible, data are mixed regarding whether hormone therapy prevents migraine during perimenopause. Migraine, including migraine with aura, is not a contraindication to hormone therapy, although the lowest effective dose necessary should be used, and estrogens may be preferred.
Loss of endogenous estrogen production during the peri- and postmenopausal periods is associated with hypertension, central adiposity, and hyperlipidemia, increasing the risk of stroke. Menopause before age 45 years, and particularly before 40 years, is associated with increased stroke risk, and so the AHA/ASA recommends screening for a history of menopause before age 45 years and modifying vascular risk factors in these patients. [KP 41] Some studies report that severe or frequent vasomotor symptoms are associated with increased risk of cardiovascular disease, but evidence of causality is lacking, and women with more severe vasomotor symptoms tend to have a higher-risk cardiovascular disease profile overall due to factors such as obesity and tobacco use.^39^
Although the Women’s Health Initiative found increased stroke risk with oral hormone therapy (conjugated equine estrogen alone or with medroxyprogesterone acetate), subsequent analyses and additional studies suggest that timing of initiation (age younger than 60 years and initiation within 5 to 10 years of menopause onset), route of administration (transdermal or intravaginal), and formulation (progestogen-only if oral) may reduce or ameliorate this risk.^80,81^ A pooled analysis of 203,767 postmenopausal women across 10 observational studies found that women with induced menopause age younger than 50 years and hormone therapy use had a lower risk of incident heart disease than those who did not use hormone therapy.^82^ Some studies demonstrate that transdermal administration, especially a low-dose (50 mcg or less) patch, may be a safer alternative to oral formulations because it bypasses first-pass hepatic metabolism.^83^ In patients with an elevated risk of stroke or history of stroke, low-dose transdermal formulations may be considered; when considering oral estrogen-containing formulations, the excess risk of stroke must be weighed against potential benefits.^39^ [KP 42]
Women with epilepsy may experience an earlier age of menopause because of hypothalamic-pituitary-gonadal axis dysfunction, particularly patients with comparatively higher seizure frequency or number of lifetime seizures.^84^ Perimenopause can also affect seizure frequency in people with epilepsy. Up to two-thirds of women reported seizure worsening during perimenopause, with seizure frequency often stabilizing or even improving in the postmenopausal period.^85^ [KP 43] Seizure thresholds can be decreased by sleep disruption due to vasomotor symptoms and due to hormonal fluctuations (particularly an elevated estrogen-to-progesterone ratio), especially in individuals with a history of catamenial epilepsy.
Although hormone therapy may offer benefits for women with epilepsy, such as reducing the risk of osteoporosis, clinicians should be aware of potential interactions with certain antiseizure medications. Exogenous estrogen can decrease serum concentrations of lamotrigine, potentially compromising seizure control. Conversely, antiseizure medications that induce cytochrome P450 enzymes can accelerate the metabolism of systemic hormone therapy, potentially reducing its effectiveness. In such cases, transdermal hormone therapy may be a preferred option because it bypasses hepatic metabolism. Women with epilepsy should be monitored closely for bone health, cardiovascular risk, and sexual dysfunction, which may be compounded by both menopause and antiseizure medication use.
Approximately 60% of women report subjective cognitive decline during perimenopause, and memory concerns are the third most frequent menopause symptom globally.^86^ The longitudinal SWAN study (Study of Women’s Health Across the Nation) and others have found a temporary, subtle decrement in verbal learning and memory during perimenopause that resolves postmenopause.^87^ Higher perimenopausal symptom burden, especially nighttime vasomotor symptoms, correlates with poorer cognitive function later in life, greater white matter hyperintensity volume, and lower amyloid β 42 to amyloid β 40 ratio levels.^88^ Earlier age of menopause, regardless of type, is also associated with cognitive decline and Alzheimer disease pathology later in life. [KP 44] For example, bilateral oophorectomy before age 46 years is associated with a 70% increased risk of dementia (HR, 1.70; 95% CI, 1.07 to 2.69), although some studies have shown that use of hormone therapy may offset this risk.^89,90^ Thus far, short-term longitudinal results from several randomized clinical trials yes testing the effects of hormone therapy on cognition in perimenopausal and early postmenopausal women demonstrated neither clear cognitive benefit nor harm, although longer follow-up is needed.^91^
Sleep disruption may contribute to cognitive dysfunction during perimenopause. Vasomotor symptoms and circadian rhythm shifts may lead to fragmented sleep, and surgical menopause is associated with increased obstructive sleep apnea risk (HR, 1.26; 95% CI, 1.15 to 1.38).^92^ Addressing sleep is essential in managing cognitive concerns in perimenopause and may include behavioral therapy, hormonal strategies, and management of comorbid conditions.
Symptoms of multiple sclerosis progression can overlap with menopause-related symptoms and age-related changes, leading to diagnostic challenges. For example, patients may report worsening fatigue, genitourinary symptoms, or cognitive dysfunction during perimenopause without corresponding radiographic evidence of multiple sclerosis disease activity. Age-related white matter hyperintensities that emerge in the postmenopausal period may be misattributed to MS, particularly in patients with long-standing disease.
Although some longitudinal studies of women with multiple sclerosis have found that the final menstrual period is associated with reduced inflammatory activity, this may also serve as an inflection point for accelerated disease progression and elevated biomarkers of neuronal injury.^93^ Vasomotor symptoms may worsen underlying multiple sclerosis symptoms by triggering the Uthoff phenomenon and by disrupting sleep. Patients who have received steroids for multiple sclerosis treatment may also be more vulnerable to osteoporosis. For these reasons, treating perimenopause symptoms, including initiating hormone therapy in patients without contraindications, may be beneficial.
This article explores the profound physiologic changes that occur during pregnancy and menopause, which may alter the course of preexisting neurologic disorders or contribute to the emergence of new neurologic conditions. Conversely, neurologic disorders and their treatment may substantially affect pregnancy outcomes and the menopausal transition. Critical gaps remain in clinical guidelines on sex- and gender-specific considerations across the lifespan. These gaps are especially evident when comparing the limited number of treatment options deemed safe during pregnancy with the expanding array available to the general population. In the absence of safety data, medications are often presumed harmful, although this assumption stems from a lack of scientific evidence, not from evidence of harm. Neurologists should remain mindful of this distinction because gaps in the current evidence may motivate ongoing research to inform future guidelines and improve care for these patients. When faced with the question, “Would my diagnostic or management approach be different if this patient were not pregnant?” (and the answer is yes), it is essential to collaborate with obstetricians, maternal fetal medicine specialists, anesthesiologists, and related clinicians and communicate risks and benefits clearly to support informed, patient-centered decision-making.
This National Library of Medicine database contains the most recent labeling submitted to the US Food and Drug Administration (FDA), which includes prescription and nonprescription drugs and devices for human and animal use.
This National Library of Medicine database provides information on medications and other substances that may be encountered during lactation, including their concentrations and potential adverse effects on nursing infants.
ncbi.nlm.nih.gov/books/NBK501922
ACOG Committee Opinion: Guidelines for Diagnostic Imaging During Pregnancy and Lactation
This committee opinion, published by the American College of Obstetricians and Gynecologists, provides guidelines for imaging during pregnancy and lactation.
The Menopause Society (formerly The North American Menopause Society)
This organization provides independent and evidence-based resources during the menopause transition and beyond.
This organization, based in the United Kingdom, provides evidenced-based resources from a wide international community.